Obesity is a chronic disease associated with high morbidity and mortality, caused by adipose tissue accumulation due to disrupted regulation of energy balance or hypernutrition. Obesity and obesity-related diseases are very serious health problems in the United States and all over the world. In the general population of the U.S., over last 7 years, the prevalence of obesity increased from 22.9% to 30.6%. According to the results from the 1999-2002 National Health and Nutrition Examination Survey (NHANES) conducted by U.S. center for Disease Control and Prevention, 29.8% of adults aged 20 years or older were overweight, 30.4% thereof were obese. The prevalence of extreme obesity among adults was 4.9% (Hedley et al., JAMA 2004; 291:2847-50). Obesity is dramatically increasing in not only the U.S. but also in every country that has adopted westernized food and cultural habits. There are currently 250 million obese people in the world, and it is estimated that about 300 million people worldwide will be obese by the year 2025. Obesity itself presents its own health problems, and is also correlated with a variety of other complications such as hypertension, hyperlipidemia, cardiovascular disease and diabetes. About 80% of obese patients have the one or more of the above diseases (Mantzoros et al., J Clin Endocrinol Metab 2000; 85:4000-2), and approximately 300,000 people die each year due to complications from obesity (Allison et al., JAMA 1999; 282:1530-8). A weight gain of just 1 kg has been shown to increase cardiovascular risk by 3.1% and diabetes risk by 4.5-9%, and about 11% weight loss has been shown to reduce the morbidity by 25%. Thus, there is an urgent need to develop therapeutic strategies for obesity (Arbeeny et al., Obes Res 2004; 12:1191-6). In 1893, for the treatment of obesity, thyroid hormone drugs were used to facilitate thermogenesis by noradrenaline and adrenaline. However, these drugs accelerated the loss of lean tissue mass and caused negative nitrogen balance to induce side effects of cardiotoxicity rather than exhibiting the desired effect of reducing adipose tissue. Thus, their use is currently limited to hypothyroidism. In the 1930s, amphetamine was used as an appetite suppressant, but its long term use was prohibited because of drug dependence. Phentermine, diethylpropion, and fenfluramine, which do not induce drug dependence, have been used for the treatment of obesity. However, their use was also prohibited, since most of them caused cardiovascular diseases, hypertension, cardiac dysrhythmia, pulmonary hypertension, and mental disorders such as failing memory. Current therapeutic strategies for obesity include appetite suppressants stimulating central adrenergic receptors or preventing resorption of serotonin, thermogenic beta 3-adrenergic agonists, digestive lipase inhibitors, and hormone regulators such as leptin and PYY (Dunstan et al., Nature reviews drug discovery 2006; 5:919-931). Among them, lipase inhibitors, orlistat and sibutramine, which prevents resorption of serotonin to suppress appetite, are the only FDA-approved drugs, but lead to side effects including steatorrhea, headache, and increased blood pressure. Thus, there are still many difficulties to develop drugs having both safety and efficacy.
GLP-1, a hormone that is secreted by the small intestine, generally promotes the biosynthesis and secretion of insulin, and inhibits the secretion of glucagon to regulate the glucose concentration in blood. It is reported that GLP-1 has the effects of suppressing food intake and reducing body weight upon administration to mice (Meeran et al, Endorinology 1999; 140:244-50), and these effects were shown in both normal and obese mice, indicating its potential as an anti-obesity agent. However, GLP-1 is rapidly degraded by the dipeptidyl peptidase IV (DPPIV), and thus its potential as a drug is very limited. On the other hand, exendin is a peptide that is found in the venom of Gila-monster common in Arizona and Mexico. It has similar physiological activity to GLP-1, but resistance to DPP IV, showing its possibility as a therapeutic agent for diabetes and obesity. Exendin is commercialized as a therapeutic agent for diabetes, which is injected twice a day. In U.S. Pat. No. 6,956,026, U.S. Pat. No. 6,989,366 and U.S. Pat. No. 7,115,569, disclosed is a method for suppressing food intake using exendin and derivatives thereof, in which the efficacy of suppressing food intake is demonstrated, but the effect maintains for 6 hrs after maximum administration. For the treatment of chronic diseases such as obesity, it needs to be injected into a patient several times a day, which is still difficult for patients. In addition, the exendin derivatives described in the patents exhibit differing efficacy, dose-dependency, and duration to each other, and do not show superior efficacy in suppressing food intake to that of native exendin.